PT91237B - PREPARATION PROCESS FOR A UNITARY, SOLID AND POROUS FORM, COMPREHENDING MICROPARTICLES AND / OR MANOPARTICLES - Google Patents

Abstract

Novel solid and porous single-dose preparation containing microparticles and/or nanoparticles, and its preparation. This novel solid single-dose preparation is applied to the administration of therapeutically active substances, nutritional agents, diagnostic agents or cosmetic agents.

Description

DESCRIPTIVE MEMORY The present invention relates to a new unitary, solid and porous form, comprising microparticles or nanoparticles, as well as to their preparation process.

The preparation of microparticles and nanoparticles is used, mainly in order to delay the dissolution of the active principles and, due to this fact, it finds numerous applications in the field of controlled release medications, as well as in the masking of taste of drugs. medicines intended for oral administration. However, it has always been very difficult to obtain a formulation containing microparticles or nanoparticles, in the form of unit doses, and in particular a formulation suitable for oral administration.

Indeed, the industrial preparation of tablets and lozenges requires quality of flow and / or cohesion of the granules to be divided, which the microparticles and / or nanoparticles do not necessarily have.

tablet poses, under the effect of compression, problems of integrity of microparticles and / or nanoparticles; its slow disintegration speed does not allow it to be administered always after disintegration and suspension in a glass of water.

The tablet does not always allow the dispersion of particles in the gastrointestinal tract.

In addition, both the tablet and the tablet pose particularly marked swallowing problems in children and the elderly.

Finally, the sachet is an expensive, non-ambulatory pharmaceutical form and the dry syrup form is often not achievable due to the early release of the active principle outside the micro and / or nanoparticles or the physical and / or chemical stability of the preparation.

French patents 2,036,890 and 2,366,835 describe for

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-4pharmaceuticals with the characteristic of rapidly dissolving or disintegrating in an aqueous medium or in saliva.

It has now been found that techniques having totally opposite objectives, such as delaying the dissolution of an active ingredient, on the one hand, and on the other hand, the fact that the pharmaceutical form disintegrates or dissolves quickly, can be associated in order to obtain a lyophilized unitary form, easily and quickly disintegrated in water, and containing microparticles and / or nanoparticles, and in which the decanting and / or coming to the surface of the particles in the course of ionization was avoided.

According to the invention, the process of preparing the new solid unitary form consists of

1) prepare a mixture of micro (and / or nano) particles containing a predetermined amount of one or more active ingredients,

2) incorporate the mixture obtained in a paste intended to be lyophilized and containing

a) at least one substance chosen from thickening and structuring materials, serving as support and ballast,

b) one or more stabilizing agents preventing the surface and / or settling of micro (and / or nano) particles in the mixture,

c) where appropriate, one or more other active ingredients or mixtures of micro (and / or nano) particles containing an active ingredient,

d) a suitable amount of water, in order to adjust the viscosity of the composition,

5) lyophilize the obtained paste.

lyophilized product obtained can be mechanically divided into unit doses with a well-defined shape and volume, but it is preferable to divide the paste into alveoli

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-5 and predetermined dimensions, prior to the lyophilization operation. The dosage of the active ingredient (s) in the paste and the shape and dimensions of the wells are calculated in order to obtain a quanti. precisely defined the active ingredient (s) in each unit dose.

In the previous description, as well as in the following, an active ingredient is any substance containing at least one therapeutically active product, a nutritional agent, a diagnostic agent or a cosmetic agent, which may be in association with one or more more than other substances of the same type or in association with other micro (or nano) particles, containing themselves other substances mentioned above.

According to the invention, a particle with a diameter between 1 u and 2 mm is called a microparticle. These microparticles can be microspheres, extruded, microcapsules or microgranules, allowing the retention of an active principle and thus avoiding complete and immediate availability by simply putting it in contact with aqueous liquid media. Any particle with a diameter of less than 1 is called a no-particle. These nanoparticles may be nanospheres or nanocapsules and have characteristics of retention of the active principle of the same nature as microparticles, it being understood that, taking into account their small size, they are susceptible to allow the transepithelial passage of the intestinal mucosa and should therefore preferably consist of bio-absorbable polymers.

The mixture of micro (or nano) particles is prepared by any known method that involves the use of a polymer or macromolecular substance. More particularly, microencapsulation techniques by solvent evaporation, microencapsulation by coacervation, microencapsulation by turbine film formation or by assembly and form, turbine film extraction, simple extrusion, extrusion-spheronization, extrusion-spheronization can be used and coating or coating in fluidized air oil.

The realization of these methods is mentioned in more detail

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-6 in the references given below, by way of example: French patent application 2,484,281

T.M. SERA3UDDIN et al., 3. Pharm. Sci., 73 (9), 1203 (1984)

L. LUZZI et al., Biochemical Applications of Microencapsulation, CRC Press, Franklin Lim Editor (1984), ch. 1, pages 1 to 19

- A.-C. VIAL-BERNASCONI et al., S.T.P. Pharma, 4 (5), 397 (1988) European patent application EP 204 596

- F. BRIQUET et al., S.T.P. Pharma, 2 (22), 986 (1936)

N. SARISUTA et al., Drug development and industrial pharmacy, 14 (5), 683 (1988) European patent application EP 193 208 French patent application FR 2 608 988

Encyclopedia of polymer Science and engineering, vol. 9, 2nd ed., John WILEY and sons inc. (1987), p. 724 to 745 Theory and Practice of Industrial Pharmacy, 2nd ed. , L. LACHMAN, H.A. LIEBERMAN and 3.L. KANIG, Ed. Lea et Febiger, Philadelphie (1976), p. 420 to 465

Formes Pharmaceutiques Nouvelles - Aspects Technologique, Biopharmaceutique et Médical, LAVQISIER Tech, et Doc., P. BURI,

F. PUISIEUX, E. DOELKER et 3.P. BENOIT, Cap. XV, p. 613 (1985).

It is understood that the polymers or macromolecular substances that can be employed are not limited to those that have been cited in the above methods. Other polymers or macromolecular substances, being the case pharmaceutically acceptable, can also be used. As an example, cellulose derivatives (cellulose, cellulose imboxyl cellulose, cellulose acetophthalate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose phthalate, for example) can be used, for example. imethacrylate, polyacrylamide, polyacrylatextran, polyalkylcyanoacrylate, for example), alginic acid, dextran, latin gas, polyethylene glycol, polyvinyl alcohol, propylene glycol alginate, starch, zelna, sucrose poly, 55

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-7 polyglycolic lactic acid, polyhydroxybutyric acid, polyamide, polyanhydride, poly-caprolactone, polydimethylsiloxane, polyiorganophosphazene, poly-ortho-esters, polyamino acids, polyyl inylpyrrol_i dona, chitin and derivatives, collagen, polyethylene, polyether , poly (vinyl chloride), polyurethanes.

A thickener and structuring material serving as a support is understood to mean any material soluble or dispersible in water, allowing to ensure the cohesion of the mass, being the case, acceptable from the pharmaceutical point of view, and inert in relation to the active principle. These materials are, inter alia, chosen from polypeptides such as gelatine or partially hydrolyzed gelatine, colloids, high molecular weight polysaccharides, high poly, which can give colloidal solutions, for example natural gums (gum arabic, gum -adraganta ...), synthetic or semi-synthetic gums (glycosylglucans, xanthan gum ...), dextran, dextrin, alginates (sodium alginate), pectj. products, cellulose derivatives (microcrystalline cellulose, carboxyl methylcellulose), hydrodispersible derivatives of starch, colloidal silicon, bentonite, or other support materials such as polyvinyl alcohol, polyvinylpyrrolidone, non-glycols polyethyl (PEG 20 000, namely PEG 6000), acrylic polymers or copolymers, or mixtures of materials such as those mentioned above.

Preferably, a water-soluble material is used.

We refer to ballast as the material, preferably soluble and crystallizable, and the case being pharmaceutically acceptable »that improve the physical properties of the new unit form. These substances can be chosen, inter alia, from lactose, glycochloride, sorbitol, mannitol, glucose, maltodextrins or even possibly from oxides (magnesium oxide), carbonates (calcium carbonate), phosphates (tricalcium phosphate), or microcrystalline cellulose, or mixtures thereof. these substances.

It is understood that the paste intended for freeze drying must, ne69 555

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-3 Optionally, contain at least one substance chosen from the thickening materials and the aforementioned ballasts, but it is also advantageous to have one or more thickening materials and one or more ballasts involved at the same time.

The thickening and structuring materials and ballast are chosen in order to give the pulp, intended for lyophilization, a rheological behavior and a viscosity suitable for a good division of the product and for maintaining the suspension in the various components (flow, homogeneity, regularity of the divided volume, suspension stability during division). These substances are also chosen in order to ensure the texture of the lyophilized final product (for example, sufficient hardness to allow extrusion through a blister) ·

The paste for lyophilization must, on the other hand, contain one or more suspending agents designed to prevent sedimentation of the micro (or nano) particles during lyophilization. These stabilizing agents are particulate, solid, micron sized substances, inert to the mixture. They can be either insoluble or soluble and in excess of the solubilizing power of the paste to be lyophilized. They are chosen in such a way that their sedimentation speed is of the same order of magnitude as that of micro (ounane) particles. The choice of the stabilizing agent is therefore adapted according to the density and size of the micro (or nano) particles, as well as the pH conditions of the solution in which it is introduced. Among the suitable stabilizing agents are oxides (titanium oxide, magnesium oxide, iron oxides, silicon, for example), salts such as carbonates (calcium carbonate, magnesium carbonate, for example), silicates ( kaolin, for example), phosphates (tricalcium phosphate, for example), sugars (lactose, glucose, mannitol, levulose, maltodextrin, for example).

In the case of nanoparticles with a density close to that of the aqueous layer of the paste to be lyophilized, it can be verified that this additive is not indispensable.

In the process according to the invention, it is understood that or69 555

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-9 date of introduction of the different substances depends on these subs.

substances in themselves, some of which may be previously mis.

turbid.

In general, the thickening and structuring materials constitute 0.01 to 99% by weight in relation to the dry mass of the lyophilisate. It is also possible to introduce only ballast and not to use thickening material.

Ballasts are generally in excess of the solubilizing power of the paste to be lyophilized. They constitute 1 to 99% by weight in relation to the total dry mass of the lyophilisate. However, it is possible to introduce only the thickener, without using the ballast.

stabilizing agent is a function of the particles it forms. they will contain the paste to be lyophilized and represent from 1 to 70% by weight in relation to the lyophilized dry mass.

The amount of water introduced is determined in such a way that the paste to be lyophilized has a reclogical length and *

adequate viscosity. It is indeed desirable to adjust the viscosity of the paste to be lyophilized in such a way that it is sufficiently fluid, to allow a regular and sufficiently viscous division, to prevent sedimentation of the micro (and / or nano) particles.

The amount of water introduced into the mix may represent 10 to 90% by weight in relation to the wet mass to be lyophilized, depending on the nature of the substances chosen for use. constitute the mixture.

Finally, the mixture of particles containing the active ingredient (s) is prepared in such a way that the introduced polymer or macromolecular substance represents 0.1 to 80% by weight with respect to the dry mass of the lyophilisate.

On the other hand, the preparation to be lyophilized may possibly contain other additives, such as surfactants or other compatible substances and, where appropriate, pharmaceutically acceptable, such as dyes, sweetening or taste-modifying substances, agents containing

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-10 preservatives and any other substance compatible with the rest of the mixture.

As an example, surfactants can be chosen from non-ionic agents (polyoxyethylene polysorbates (Tuieen), sorbitan esters (Span), ethylene oxide and propylene copolymers, polyoxyethyl ethers and fatty alcohol , ...), anionic agents (esters of sulfo-succinic acid: dialkyl sulfo-succinate, for example sodium dioctyl-suphosuccinate), cationic agents (quaternary ammonium salts).

The sweetening or taste-modifying substances can be, inter alia, sucrose, glucose, xylose, the sortá tol, saccharin, saccharinates, cyclamates, aspartame, ammonium glycyrrhizinate, or even citric, ascorbic or tartaric acid, or any other substance commonly used for the modification of taste in the food or pharmaceutical industry and which is compatible with the products in question.

All these substances can be added, regardless, at the beginning, in the course or at the end of the constitution of the paste to be lyophilized.

It is understood that this new unitary, solid form can be applied to the administration of all types of substances and more especially to the active pharmaceutical ingredients that can be used orally and intended for both human and veterinary medicine. It also applies to nutrition agents, diagnostic agents and cosmetic agents.

As an example, among the pharmaceutically active substances that can be administered in this form, anti-infectives (spiramycin, pristinamycins, tetracyclines, metronidazole, pefloxacin and quinolone family derivatives, fixin, josamycin, anti-inflammatories and anti-inflammatories and anti-inflammatories) -reumatismals (ketoprofen, ...) analgesics (aspirin, paracetamol, clomethacin, ...) tranquilizers (lorazepam, oxazepam, zopiclone and other derivatives of the cyclopyrrolone family, derivatives of the phenothiazine family), cardiovascular and vasodilated69 555

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-11 brain cells (isosorbide dinitrate, trinitrin, dihydroergotoxin, digoxin, quinacaine, propranolol, oxyprenolol, vincamine, nicergoline, ...) brain protectors (eg gangliosides), anti-spasmodics and anti-secretors, anti - somatic, therapeutic agents for diseases of the gastrointestinal tract, liver protectors, hormones, contraceptives, medicines for the treatment of allergies, vaccines, vitamins, or even peptides, polypeptides or proteins.

Among the nutritional agents, amino acids can be mentioned, for example, methionine, lysine, carnitine lysinate ...

The new unitary, solid form also applies to in vitro diagnostic agents, for example, acridine orange (phagocytosis marker), or to in vivo diagnostic agents.

When the new solid unitary form is applied to cosmetic agents, the active principle is chosen, namely, from the substances that modify the breath, such as menthol and essences of mint or eucalyptus.

The amount of active ingredient introduced varies according to its nature, but it is understood that this new solid form may allow the preparation of unit doses with a high content of active ingredient, thus allowing to reduce the multiplicity of doses, taking into account the controlled release.

In general, the amount of active ingredient can be up to 95% by weight with respect to dry matter.

The new solid form according to the invention thus has the advantage of combining a unitary main form with instantaneous disintegration in aqueous medium, with a secondary form with controlled dissolution consisting of a system of micro (and / or nano) particles.

The main shape allows easier use, in particular avoids the agglomeration of particles and has, above all, the advantage of containing a predetermined amount of active ingredient.

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-12Α secondary form controls the release of the active principle on contact with aqueous media. It is particularly intended for substances that are unstable in solution. For example, when the active ingredient is intended for oral administration, the micro (and / or nano) particle shape allows to control the availability of the active ingredient; the substance is protected until the desired zone or until the desired moment. The release of the active matter is thus linked to factors such as pH, ionic strength, the presence of an enzyme, the presence of specific bacterial flora or not. The choice of the size of the micro (and / or nano) particles allows predetermining the speed of release of the active principle; for example, the rate of release into the gastrointestinal medium, when the active ingredient is administered orally. This secondary form may, of course, contain several series of micro (or nano) particles, either mixed with each other and in which the active substances will be released simultaneously or successively, or contained in each other and in which the active substances will be released successively. The secondary shape also allows the taste of active substances to be masked, for example bitter products.

The new unitary, solid form according to the invention, when applied to pharmaceutical formulations, is therefore very especially suitable for oral administration, but can also be used for rectal or vaginal administration.

Taking into account the advantages it presents, the new unitary, solid form, according to the invention, is very special, especially indicated for oral pharmaceutical formulations for pediatrics or geriatrics, for formulations with bio-adhesion bju cal as per example the systems to freshen the breath ..., for formulations for colonic vectoring ... or even in veterinary medicine, in the case of feeding aids and in the cases of medical diagnoses.

The following examples illustrate the present invention.

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-13EXEHPLO 1

Preparation of a lyophilisate containing pyramicin microspheres 50 to 400 yx in diameter:

a) 33 g of base spiramycin and 27 g of Eudragit E 100 are dissolved in 100 cm of dichloromethane. The solution obtained is called solution A.

b) 14 g of poly (vinyl alcohol) (Mowiol 8.98 from Hoechst) 3 g of spiramycin base and 70 g of sodium chloride are dissolved in 700 cc? of water. The solution obtained is called solution B.

c) Solution A is dispersed in solution B, under mechanical stirring. Stirring is continued until removal of the organic solvent, i.e. 10 hours at room temperature.

d) The microspheres obtained are filtered, washed and dried (50 g of dry matter). This gives a pale yellow powder, the taste of which is tasteless. Microscopic examination reveals individualized and spherical microparticles 50 to 400 in diameter. Its spiramycin content is about 55%.

e) Spiramycin microspheres previously obtained are mixed dry with 46 g of mannitol and 17 g of titanium oxide.

f) Is a fluid gel prepared by dissolving 35 mg of xanthan gum, 5 g of dextran 70 and 250 mg of sodium dioctyl sulfosuccinate in 76 cm? of water.

g) This fluid gel is added to the mixture of the powders prepared in e) and the mixture is stirred under reduced pressure (about 0.1 bar). A slurry of about 635 mPa.s of relative viscosity is obtained in the 44 s shear gradient (coaxial viscometer).

h) Is the paste divided into 1.2 cm transparent poly (vinyl chloride) wells? at the rate of 1150 + _ 57.5 mg.

i) Freeze the paste in a freeze dryer at -2590, then freeze for 5 hours: the product temperature goes from -25 to +4090. The wells are heat-sealed with a sheet of com69 555

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-14 aluminum-poly (vinyl chloride) complex -poly (vinyl dichloride).

lyophilisate obtained contains 750 000 IU of spiramycin. Its taste is tasteless. Its mechanical strength allows extraction out of the small thermoformed plate and manipulation until the time of administration.

disintegration time of the lyophilisate in water, varies from 1 to 3 minutes. The microspheres do not release spiramycin after 15 minutes in a glass of water; they release spiramycin in media with a pH below 5, such as gastric juice, for example.

EXAMPLE 2

It operates as in example 1 from a) to d), for the preparation of spiramycin microspheres.

e) Spiramycin microspheres previously obtained are mixed dry with 46 g of mannitol, 8.5 g of titan oxide. and 0.5 g of calcium carbonate.

A fluid gel was prepared as in example 1, f), and the powders prepared in e) were added to the mixture. The obtained paste is divided into wells and lyophilized as previously described in example 1.

EXAMPLE 3

It operates as in example 1 from a) to d) for the preparation of spiramycin microspheres.

e) Spiramycin microspheres previously obtained are mixed dry with 46 g of mannitol, 8.5 g of titanium oxide and 0.5 g of tricalcium phosphate.

A fluid gel was prepared as described in example 1 f) and the powders prepared in e) were added to the mixture. The obtained paste is then broken into alveoli and lyophilized as described previously in example 1.

EXAMPLE 4

It operates as in example 1 from a) to d) for the preparation of spiramycin microspheres.

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-15e) The spiramycin microspheres previously obtained are mixed dry with 46 g of mannitol, 8.5 g of titanium oxide and 8.5 g of kaolin.

A fluid gel was prepared as described in example 1 f) and the powders prepared in e) were added to the mixture. The obtained paste is divided into wells and lyophilized as previously described in example 1.

EXAMPLE 5

It operates as in example 1 from a) to d) for the preparation of spiramycin microspheres.

e) Spiramycin microspheres previously obtained are mixed dry with 46 g of mannitol and 17 g of tricalcium phosphate.

A fluid gel was prepared as described in example 1 f) and the powders prepared in e) were added to the mixture. The obtained paste is re-divided into wells and lyophilized as previously described in example 1.

EXAMPLE 6

It operates as in example 1 from a) to d) for the preparation of spiramycin microspheres.

e) Spiramycin microspheres previously obtained are mixed dry with 46 g of mannitol and 17 g of kaolin.

A fluid gel was prepared as described in example 1 f) and the powders prepared in e) were added to the mixture. The obtained paste is re-divided into wells and lyophilized as previously described in example 1.

EXAMPLE 7

Preparation of a lyophilisate containing spiramycin microspheres from 50 to 150 in diameter.

a) 66.6 g of spiramycin base and 55.4 of ethyl cellulose (Hercules quality N 100) are dissolved in 700 cm ^ of diclo

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-16romethane. The solution obtained is called solution A.

b) 45 g of poly (vinyl alcohol) (Mowiol 6.38 from Hoechst), 9.5 g of spiramycin base and 225 g of sodium chloride are provided in 2100 cm @ 3 of water. The solution obtained is called solution B.

c) Solution A is dispersed in solution B under constant mechanical stirring (350 revolutions / minute) and the stirring is continued until the organic solvent is eliminated, ie 18 hours at ambient temperature.

d) Fractions greater than 150 and less than 50 p are eliminated by wet sieving. The 50-150 p fraction is washed and dried. Thus 72.5 g of a pale yellow powder are obtained, consisting of individual and spherical microspheres of 50 to 150 p in diameter. Its taste is tasteless. Its spiramycin content is about 66.7%.

e) Spiramycin microspheres previously obtained are mixed dry with 130 g of mannitol and 15 g of titanium oxide.

f) Was a fluid gel prepared by dissolving 40 mg of xanthan gum, 2.9 g of dextran and 73 mg of sodium dioctyl sulfosuccinate in 135 cm? of water.

g) This fluid gel is added to the powder mixture prepared in e) and the mixture is stirred under reduced pressure (about 0.1 bar).

h) The paste is divided into 1.2 cm transparent poly (v / nile chloride) wells at a rate of 1200 mg.

i) Freeze the paste in a freeze dryer at -2590 and then lyophilize for 5 hours; the product temperature goes from -25 to +4090. The wells are heat-sealed with a sheet of aluminum-poly (vinyl chloride) -poly (vinyl dichloride) complex.

lyophilisate obtained contains 750 000 IU of spiramycin. Its taste is tasteless. Its mechanical resistance allows extrusion outside the alveoli of the small thermoformed plate and handling until the moment of administration.

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-170 time of disintegration of the lyophilisate in water varies from 15 to 50 seconds. The microspheres do not release spiramycin in a glass of water after 15 minutes; they release spiramycin in pH less than 5, such as gastric juice, for example.

EXAMPLE 8

Preparation of a lyophilisate containing acridine orange nanospheres from 100 to 200 nm in diameter. Acridine orange is used in this example for in vitro diagnostic purposes of phagocytosis of nanoparticles by macrophages.

a) 0.001 g of acridine orange and 0.5 g of poly (1-acetic acid-D, L) (PLA 50 of molecular weight 49 000 from RhÔne-Poulenc) are dissolved in 100 cn? acetone. The solution obtained is called solution A.

mixed

b) 0.5 g of polymer / ethylene and propylene oxide (R)

-glycol (Pluronic F 68 or Poloxamer 188 ^ are dissolved in 3

200 cm of distilled water. The solution obtained is called solution B.

c) Solution A is emulsified in solution B by stirring a bar at a speed of 100 revolutions per minute.

d) Stirring is maintained for 24 hours at room temperature and atmospheric pressure in order to remove acetone by evaporation.

e) The obtained suspension is filtered through a 0.8 porosity filter.

f) Centrifuge at 10,000 revolutions per minute for 1 hour and then remove 155 cm ³ of supernatant. This results in a pellet of acridine orange nanospheres (about 0.5 g) redispersible in the remaining 45 cm3 of aqueous phase. Microscopic examination reveals individualized and spherical nanoparticles of 100 to 500 nm in diameter. Its acridine orange content is about 0.2%.

g) Is the nanosphere sediment previously obtained dispersed again in the 45 cn? of remaining aqueous phase. 12.5 mg of xanthan gum (Rhodigel 25 from Rhone-Poulenc) and 1 g of dex are added.

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-18tran 70 and stirred until a fluid gel is obtained.

h) 10 g of titanium oxide are mixed dry with 62 g of mannitol.

i) The fluid gel prepared in g) is added to the powder mixture prepared in h) and the mixture is stirred under reduced pressure (about 0.1 bar).

j) Is the paste divided into 1.2 cm transparent poly (vinyl chloride) wells? at the rate of 1200 mg.

k) The paste is frozen at -2520 in a freeze dryer and then freeze dried for 5 hours; the product temperature goes from -25 to + 40 ° C. The blisters are heat-sealed with a sheet of aluminum-poly (vinyl chloride) -poly (vinyl dichloride) complex.

lyophilisate obtained contains about 0.01 mg of acridine orange. Its mechanical resistance allows extrusion outside the alveoli of the small thermoformed plate and handling until the moment of administration.

disintegration time of the lyophilisate in water is less than 1 minute.

EXAMPLE 9

Preparation of a lyophilisate containing microgranules of p_a racetamol of 0.8 to 1.6 mm in diameter.

a) 182 g of paracetamol (powdered quality, Rhone-Poulenc) are mixed dry with 728 g of microcrystalline cellulose (Avicei PH 101 quality from FMC corp.).

b) The preceding mixture is wetted with 6 liters of 1.5% aqueous solution of sodium carboxymethylcellulose.

c) The wet mass is extruded on a 1 mm grid and then spheronized for about 5 minutes.

d) Dry in an oven at 3520 ° C.

e) The fraction with a diameter between 1 and 1.5 mm is selected by sieving. Approximately 900 g of micrograin are obtained

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-19 spherical non-paracetamol beads between 1 and 1.5 mm in size (yield of about 90%).

f) In a fluidized air bed apparatus, the 1800 g of the previous solution is sprayed on the 900 g of microgranules obtained in e):

Ethylcellulose, 30% aqueous dispersion ......... 50.0 g (Aquacoat EDO 30 from FMC Corp.)

Diethyl phthalate .................. 3.0 g

Yellow iron oxide ................ 0.4 g

Distilled water .................... 46.6 g

Approximately 1 kg of long-release microgranules of paracetamol with a diameter between 0.8 and 1.6 mm and brown in color are obtained. Its content of paracetamol is about 15.2%.

g) 110 g of coated microgranules, of paracetamol, previously obtained in f) are mixed dry with 96 g of mannitol and with 33 g of titanium oxide.

h) A fluid gel was prepared by dissolving 500 mg of xanthan gum (Rhodigel 23 from Rhone-Poulenc), 500 mg of dioctyl sulfo-succinate and 10 g of 70 dextran in 150 cm) of water.

i) This fluid gel is added to the powder mixture prepared in

g) and the mixture is stirred under reduced pressure (about 0.1 bar)

j) The paste is divided into 1.2 cm ³ transparent poly (vinyl chloride) wells at a rate of 1200 mg.

k) The paste is frozen at -25 ° C in a freeze dryer and then freeze dried for 5 hours; the product temperature goes from -25 to + 40 ° C. The wells are heat-sealed with a sheet of aluminum-poly (vinyl chloride) -poly (vinyl dichloride) complex.

lyophilisate obtained contains 50 mg of paracetamol. Its mechanical strength allows extrusion out of the small thermoformed plate and handling until the moment of administration.

disintegration time of the lyophilisate in water varies from 1

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-20 to 5 minutes. Prolonged-release microgranules practically do not release paracetamol during the disintegration of the filtered phyllo in aqueous media.

The release of paracetamol from the microgranules is controlled by a polymeric membrane.

The kinetics of paracetamol dissolution in vitro are controlled by method n9. 2 in the palette described at USP XXI is represented by the results grouped in the table together.

PARACETAMOL DISSOLUTION KINETICS IN VITRO FROM PROLONGED RELEASED MICROCRANULES (USP XXI method on palette No. 2 - 3790 - 120 revolutions / minute - medium pH 1 = HCl 0.1 N - medium pH 7.4 = solution disodium phosphate / citric acid buffer - UV spectrophotometer reading at 242 nm).

DISSOLUTION MEANS TIME PERCENTAGE DISSOLVED 0.1 N HCl pH 1 30 minutes 3.5% 1 hour 5.0 / 2 hours 8.5 / PH 7.4 buffer 3 hours 13.5 / 4 hours 17.5 / 5 hours 32.0 / 6 hours 5 0.5 / 7 hours 6 5 f 0 / □ 8 hours 77.5 / 24 hours 100.0 /

EXAMPLE 10

Preparation of an oral lyophilisate containing ketoprofen microspheres.

a) 60 g of ketoprofen and 240 g of a mixture of ethylce69 555

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-21lulose / Eudragit RS 100 (9: 1) are dissolved in 1.5 liters of dichloromethane with the aid of a paddle stirrer (Heidolph) at 500 rpm / minute.

*

b) The preceding solution is added 1.5 liters of an aqueous solution of Méthocel K4M at 0.27 / (weight / volume) to obtain an emulsion.

c) After evaporation of the dichloromethane under reduced pressure, the microspheres are separated by centrifugation and washed with 3 liters of water.

The microspheres are dried at room temperature for 2 to 3 hours in a fluidized air bed apparatus.

d) 500 mg of the microspheres obtained as described above (dosed at 20.2 / in active ingredient) are mixed dry with:

xanthan gum (Rhodigel 23 from Rhone-Poulenc) .... 0.75 mg sodium dioctyl sulfosuccinate ........... 0.38 mg

Dextran 70 ...................... 30.00 mg

Lactose ....................... 218.87 mg and then added with 500 mg of water.

e) The paste is divided into polyvinyl chloride wells and then lyophilized under the conditions described in the preceding examples.

lyophilisate obtained contains 100 mg of ketoprofen.

disintegration time of the lyophilisate is 1 minute and 20 seconds.

Claims (5)

rfclaims 1) prepare a mixture of micro (and / or nano) particles containing a predetermined amount of one or more active ingredients, 1 - Process of preparation of a unitary, solid and porous form characterized by the following steps: Process according to claim 1, characterized in that said unitary form is obtained in a form suitable for oral administration. 2) incorporate the mixture obtained in a paste intended to be lyophilized and containing a) at least one substance chosen from the thickening and structuring materials that support it and the ballasts b) one or more stabilizing agents, preventing the decari- tation and / or the surface of micro (and / or nano) particles containing an active ingredient, c) eventually, one or more other active ingredients or mixtures of micro (and / or nano) particles containing an active ingredient, d) an adequate amount of water, in order to adjust the viscosity of the composition, Process according to claim 1, characterized in that the unitary form is obtained in a form suitable for rectal or vaginal administration. 3) lyophilize the paste obtained, possibly after distribution in wells of predetermined shape and dimensions, 4 - Process according to claim 1, characterized 69 555 ΧΤ. 580 FL / DL - 1127/89 -23 because the active ingredient is a therapeutically active substance. 4) eventually, dividing the lyophilisate into unit doses, of predetermined shape and volume. Process according to claim 1, characterized in that the active ingredient is a nutrition agent, a diagnostic agent or a cosmetic agent.